Gastroparesis is a gut-motility disorder characterized by delayed gastric emptying in the absence of mechanical gastric outlet obstruction. The cardinal symptoms of gastroparesis include nausea, vomiting, early satiety, bloating, and abdominal pain. The proposed mechanisms of gastroparesis are heterogeneous but include impaired gastric accommodation, gastric arrhythmia, antral hypomotility, duodenal dysmotility, pyloric sphincter spasm, autonomic dysfunction, and visceral hypersensitivity, in isolation or in combination.^1-4 Among these, pyloric dysfunction has received increased attention due in part to the growing recognition of the role of the pylorus on the development of gastroparesis symptoms, but also secondary to the emergence of newer diagnostic and therapeutic modalities such as functional luminal impedance planimetry (FLIP) and gastric peroral endoscopic pyloromyotomy (G-POEM).

Historically since the 1940s, pylorospasm with gastric outlet obstruction physiology was a well-known complication of truncal vagotomy in the treatment of peptic ulcer disease.⁵ Pyloric dysfunction in non-surgical gastroparesis was first described in 1986 from manometric analysis of patients with diabetic gastroparesis.⁶ In that study, unusually prolonged (≥3 minutes) and intense (≥10 mm Hg) tonic contraction of the pylorus measured with conventional manometry, defined as pylorospasm, was observed in 14 of the 24 patients with diabetes presenting with nausea and vomiting. Subsequently, a small number of studies reported pylorospasm in patients with gastroparesis, although the etiology remained poorly elucidated.^7-9 Currently, pylorospasm is considered a pathological phenomenon without definite diagnostic criteria or established treatment approaches. This review aims to expound on pyloric dysfunction resulting in gastroparesis, focusing on its pathophysiology and potential diagnostic and treatment modalities based on published studies.

1. Anatomy and function

The pylorus is a short section of the gastroduodenal junction with thickened muscularis creating a high-pressure sphincter that plays a key role in the gastric passage of food material. In humans, food ingestion of >250 kcal induces proximal stomach relaxation to serve as a food reservoir without an increase in intragastric pressure.¹⁰ A steady increase in fundic tone then pushes the food material into the distal stomach with short-lived transient pyloric openings allowing the passage of only small volumes of fluid and tiny solid particles to the duodenum. When food reaches the gastric body, waves of peristaltic activity then travel antegrade across the gastric body to the antrum to propel food forward.¹¹ When these waves of gastric muscle contractions reach the terminal antrum, the pyloric sphincter is closed, resulting in the backward movement of the majority of food material. This process allows the distal stomach to grind the food material into small particles, in a process known as the “antral pump,” here-in allowing food to be ground, and mixed with gastric secretions via repetitive peristaltic contraction.¹¹ Only after the trituration of the food material into particles smaller than 2 mm, is the pylorus relaxed and gastric emptying occurs with antro-pyloro-duodenal coordination.¹² The pylorus acts not only as a sieve for solid food but also as a gatekeeper for liquid emptying.¹³

2. Innervation and regulation

Several in vitro studies have revealed two distinctly innervated areas of the pyloric musculature: the luminal circular muscle close to myenteric plexus and the serosal circular muscle regulated by vagal-mediated motor neurons.¹⁴ The circular muscle is dominated by gastric slow-wave propagations. However, antral slow waves are not propagated into the pyloric circular muscle. Therefore, the two regions are independently controlled, which may underlie the regulation of the timing and function of “pyloric resistance.”¹⁵

Although the pyloric sphincter is located at the junction between the stomach and duodenum, the pyloric sphincter muscle is continuous with the circular muscle of the antrum but, not with the circular muscle of the duodenum.¹⁶ In addition, both the electrical and mechanical behaviors of the stomach and pylorus are separated from those of the duodenum. Different slow waves are generated and propagated from interstitial cells of Cajal (ICC) in the stomach and the small intestine.¹⁷ Compared to the gastric body, the pylorus exhibits a reduced network of ICC, a source of peristaltic gastric slow waves,¹⁸ termed the slow wave-free zone. This hinders the propagation of gastric slow waves to the duodenum.¹⁹

Pyloric activity is regulated by intrinsic (i.e., enteric) and extrinsic (i.e., central, autonomic) innervation.⁴ The intrinsic innervation is supplied by the myenteric plexus of the stomach which extends through the pylorus. The enteric nervous system controls the tonic contraction of the proximal stomach and the phasic contraction of the distal stomach.¹⁴ Excitatory motor neurons release acetylcholine and tachykinin whereas inhibitory motor neurons release nitric oxide (NO), vasoactive intestinal peptide, pituitary adenylate cyclase-activated peptide, and purines.¹⁴ Motor neurons innervate the smooth muscle cells and form an electrical syncytium with two types of interstitial cells; ICC and the platelet-derived growth factor receptor alpha (PDGFR-α)-positive fibroblast-like cells.^14,20,21 Intramuscular ICC transduce cholinergic excitatory and nitrergic inhibitory neurotransmission, whereas PDGFR-α-positive cells mediate purinergic inhibitory neurotransmission.^22-24 Nitrergic neurotransmission is the main inhibitory pathway in the pyloric sphincter.^22,25 The loss of ICC or NO synthase leads to the absence of nitrergic pyloric relaxation and induces pyloric dysfunction.^18,26 The extrinsic innervation of the pylorus is provided mainly by the branches of the vagus nerve, carrying mostly sensory afferent fibers. Traditionally, parasympathetic motor nerves were thought to exert an excitatory effect whereas sympathetic motor nerves exert an inhibitory effect on the stomach. However, it has been elucidated that the vagus nerve exerts both excitatory and inhibitory effects on gastric motility via sensory-motor circuits, and the sympathetic nerves have a limited role.²⁷ Afferent sensory nerve fibers of the vagus end in the nucleus tactus solitarius and communicate with the dorsal motor nucleus from which the efferent motor nerve fibers originate.⁴ Electrical stimulation of vagal sensory nerve fibers reduces pyloric resistance and increases the transpyloric flow rate.²⁸ Denervation of the pylorus by vagotomy results in reduced compliance and in the loss of pyloric relaxation.²⁷ Due to the high density of stretch receptors, the threshold for a stretch response is lower in the pylorus than in the antrum.²⁹ Pyloric contraction is also regulated by the enterogastric vasovagal reflex. The frequency and amplitude of the phasic contractions of the pylorus increase following the instillation of acid into the duodenum,^30,31 indicating that vagal sensory fibers in the duodenum initiate a signal to the vagal central nuclei, which is propagated back via vagal motor cholinergic neurons in the pylorus.

Current evidence supports several mechanisms that may result in pyloric dysfunction (Table 1). Autonomic neuropathy is classically associated with the pathogenesis of diabetic gastroenteropathy related to the susceptibility of small or unmyelinated autonomic nerves to vascular or metabolic insult.³² In a large study including 242 patients with gastroparesis and chronic nausea and vomiting, both sympathetic and parasympathetic dysfunction was identified, with more severe symptoms associated with higher rates of parasympathetic dysfunction.³³ While classically associated with oxidative stress from hyperglycemia, autonomic dysfunction and subsequent alterations in gastric motility have been observed in patients with multiple systemic atrophy and Parkinson’s disease related to neuronal damage from alpha-synuclein deposition.³⁴

Table 1 . Summary of the Mechanisms of Pyloric Dysfunction.

Mechanism	Comments
Autonomic neuropathy	• Vascular, metabolic or toxic insult to small or unmyelinated autonomic nerves of the pylorus leads to autonomic neuropathy mediated gastroparesis E.g., diabetic gastroparesis, Parkinson’s disease
Vagal nerve injury	• Extrinsic innervation of the pylorus is supplied by branches of the vagus nerve • Denervation leads to decreased compliance and pylorospasm E.g., postsurgical gastroparesis (gastric vagotomy, thoracic surgery)
Loss of ICC	• Intrinsic innervation of pylorus and subsequent signaling is mediated through gastric pacemaker cells, ICC • Loss in motor signal conduction to pyloric smooth muscle by enteric motor neurons leads to antral hypomotility and pylorospasm E.g., idiopathic gastroparesis, diabetic gastroparesis
Loss of nNOS	• Nitrergic neurons innervate both myenteric and submucosal layers of pyloric muscle • Alteration in post-junctional nitrergic response leads to loss of nNOS thereby causing abnormal pyloric relaxation and altered gastric emptying E.g., pyloric sphincter hypertrophy
Smooth muscle degeneration/ atrophy and fibrosis	• Reduced smoothelin expression and altered mRNA levels of smooth muscle contractile protein • Histology with circular muscle atrophy and intramuscular fibrosis • Mostly studied in gastric body and definitive role in pylorospasm requires further investigation E.g., scleroderma

ICC, interstitial cells of Cajal; nNOS, Neuronal nitric oxide synthase; mRNA, messenger RNA..

Reported observations in patients undergoing various vagotomy approaches have provided an important understanding of possible vagal dysfunction as a source for pyloric pathophysiology. In the 1940s to 1970s when truncal vagotomy was commonly performed for the treatment of gastric ulcers, high rates of delayed gastric emptying were noted, necessitating, concurrent pyloromyotomy during all vagotomy cases to allow sufficient post-procedural gastric emptying.³⁵ Postoperative delayed gastric emptying has also been reported after various surgeries including esophagectomy, hiatal hernia repair, anti-reflux surgery, bariatric surgeries, lung transplantation and pylorus preserving pancreaticoduodectomy.^7,36-38 While pyloric dysfunction secondary to vagal nerve injury is suspected to be the main mechanism in these surgeries, there is no proper pyloric diagnostic modality to assess it. Desprez et al.³⁹ evaluated, pyloric distensibility and pressure using the EndoFLIP system (Crospon Ltd., Galway, Ireland) in patients who developed dyspeptic symptoms after anti-reflux surgery, sleeve gastrectomy, or esophagectomy. In cases where the surgeons used a threshold of 10 mm²/mm Hg of pyloric distensibility at 40 mL of inflation, altered fasting pyloric distensibility was observed in patients undergoing esophagectomy or Nissen fundoplication but not sleeve gastrectomy. The rate of altered fasting pyloric distensibility was particularly high (75%) in patients undergoing esophagectomy, and vagal damage following esophagectomy and gastric tubulization was considered the cause of pyloric denervation. However, pyloric dysfunction and/or delayed gastric emptying are not found in all patients with dyspeptic symptoms who undergo these surgical procedures. Further studies on diagnostic tools assessing postoperative vagus nerve injury and the correlation between the degree of the injury and pyloric dysfunction are warranted to address these questions.

The loss of ICC has been proposed as an additional mechanism for gastroparesis-associated pylorospasm, based on its observation in full-thickness gastric biopsy specimens in patients with diabetes and idiopathic gastroparesis.^40,41 Damage to the myenteric ICC network has been suggested to induce antral hypomotility, with intramuscular ICC damage subsequently inducing pylorospasm.¹⁴ In a study describing histologic abnormalities in patients with gastroparesis, ICC loss was the most common finding in the gastric body; this finding was also observed in full-thickness pyloric biopsies, and the rate of ICC reduction was high (83%) in patients with gastroparesis.⁴² Interestingly, the symptom score was higher in patients with gastroparesis and pyloric ICC loss than in those with normal numbers of ICC.^42,43 It is postulated that the loss of ICC is secondary to an inflammatory cascade leading to a switch from anti-inflammatory M2 macrophages to proinflammatory M1 macrophages which suggest macrophage-driven immune dysfunction might give rise to ICC damage.^10,40 However, the underlying trigger behind this inflammatory cascade is currently unknown.

Studies in animal models have revealed that pyloric dysfunction is associated with loss of the neuronal nitric oxide synthase (nNOS) activity or the reduction of tissue nNOS expression.^44-46 NO is a crucial cellular signaling molecule that modulates nonadrenergic, noncholinergic nerve-mediated smooth muscle relaxation in the gastrointestinal tract⁴⁷ with the pyloric sphincter exhibiting the highest levels of nNOS expression among all investigated gastrointestinal tissues.⁴⁸ Huang et al.⁴⁹ reported that the knockdown of nNOS in mice led to significantly enlarged stomachs with concurrent pyloric sphincter hypertrophy. Similar findings were observed in infants with hypertrophic pyloric stenosis⁵⁰ with histologic examination noting enlarged and distorted enteric nerve fibers without nNOS within the pyloric tissue.⁵¹

Smooth muscle degeneration/atrophy and fibrosis has also been linked to the development of pyloric dysfunction.^42,52 Molecular changes such as reduced smoothelin expression and altered messenger RNA (mRNA) levels of smooth muscle contractile protein have been reported with higher rates of circular muscle atrophy and intramuscular fibrosis noted on histologic assessments.^10,40,52 However, the majority of these studies focused on gastric body dysmotility, and few studies have investigated the pathophysiology of pyloric dysfunction directly. Thus, whether these findings are unique to a specific subset of patients with pylorospasm or are more universal findings requires further cellular and molecular investigations.

In clinical practice, the diagnosis of pyloric dysfunction remains challenging due to the lack of specific symptoms and the limited number of diagnostic techniques, most of which are invasive. Symptoms of pyloric dysfunctions can be similar to those of gastroparesis, although certain symptoms such as nausea, vomiting, and abdominal pain/discomfort are commonly reported in patients with pyloric dysfunction.^6,8 Pyloric dysfunction can be asymptomatic, given that it is also observed in healthy volunteers without upper gastrointestinal symptoms.⁶ Endoscopic examination may suggest the spasm or tightening at the pylorus; however, the interpretation of such findings can be subjective, and the findings can be affected by multiple factors such as the degree of gastric air inflation, type of sedation, and the observation duration.⁵³ Fluoroscopy, which has been historically used to evaluate pyloric canal diameter has the limitations of subjective interpretation subjectivity and the lack of clinical objective criteria to distinguish abnormalities.⁵³ Solid meal 4hr gastric emptying scintigraphy is considered the gold standard test for the diagnosis of gastroparesis in patients with upper gastrointestinal symptoms;⁵⁴ however, the data on its utility in assessing pyloric function are lacking. Summary of diagnostic methods for evaluating pyloric dysfunction is shown in Table 2.

Table 2 . Summary of Diagnostic Methods for Evaluating Pyloric Dysfunction.

Method of evaluation	Pros	Cons
Wireless motility capsule	• Orally ingested • Provides real-time measurements of temperature, pH, and pressure of gastrointestinal tract • FDA approved to measure gastric emptying • Patient comfort • Concurrent evaluation of small bowel and colon transit.	• Difficult to differentiate between migratory motor complex over physiologic slow emptying of a meal • Not extensively studied for antral and pyloric pressure
Body surface gastric mapping	• Noninvasive • Results grouped by phenotypes with specific pathophysiologic conditions	• Does not provide direct information on pyloric function
High-resolution manometry	• Ability to characterize dysfunctions of postprandial antral contractility and pyloric motility	• Technically difficult
EndoFLIP	• Measures distensibility and compliance of pyloric sphincter • Can be used to predict response to pylorus-targeted therapies	• Wide variations in distensibility among healthy individuals

FDA, Food and Drug Administration..

1. Wireless motility capsule

The wireless motility capsule (WMC; SmartPill, Medtronic, Minneapolis, MN, USA) is an orally ingested recording device that provides real-time measurements of temperature, pH, and pressure of its surroundings in the gastrointestinal tract.⁵⁵ The device has been approved by the U.S. Food and Drug Administration for the evaluation of gastric emptying in patients with gastroparesis, colonic transit in patients with constipation and whole gut dysmotility. Important advantages of the WMC include the relative comfort to the patient and the ability to concurrently examine the small bowel and colon transit. A disadvantage is that as a large un-dissolvable object, the transit of the capsule from the stomach to the intestine largely reflects the occurrence of a migratory motor complex to clear the stomach, rather than the physiologic slow emptying of a meal. However, the WMC can provide information on the pressure in the stomach. Kloetzer et al.⁵⁶ used WMC to measure the antroduodenal pressure profiles of 71 healthy volunteers and 42 patients with gastroparesis and demonstrated that the frequency of antral contractions and the motility index were decreased in patients with gastroparesis compared to the healthy volunteers. However, no study to date has utilized the WMC to measure pyloric pressure. The ability to utilize WMC to accurately measure antral and pyloric pressure profiles in addition to the gastric emptying time will be useful to more precisely determine the pathologic lesions giving rise to gastroparesis.

2. Body surface gastric mapping

Body surface gastric mapping (BSGM), a new method evolved from noninvasive electrogastrography,^57,58 provides a comprehensive spatial analysis of gastric potentials via a dense grid of cutaneous electrodes and sophisticated signal processing systems designed for gastric electrophysiology.⁵⁹ Gastric Alimetry (Alimetry, Auckland, New Zealand) is a commercial BSGM product including a high-resolution electrode array, a wearable reader, an iPadOS application for setup and symptom logging, and a cloud-based analytics and reporting platform.⁶⁰ The standard Gastric Alimetry test consists of fasting preprandial recording(30 minutes), meal (10 minutes), and postprandial recording (4 hours).⁶¹ The eight phenotypes based on the spectral and symptom features obtained with the Gastric Alimetry test include dysrhythmic; low-amplitude; high-amplitude; low-frequency; high-frequency; and sensorimotor, continuous, and post-gastric profile.⁶² Each phenotype suggests specific pathophysiologic conditions that should be considered. In a recent study by Gharibans et al.,⁶³ the device was able to identify specific disease phenotypes in patients with chronic nausea and vomiting. Although it does not provide direct information on pyloric function, Gastric Alimetry may guide management principles by differentiating the pathophysiology of gastroparesis. Pyloric targeted therapies have been reported to be efficient in patients with gastroparesis and normal gastric electrical activity of 3 cycles/min during low-resolution electrogastrography.^64,65 Importantly, clinical trials (NCT05789511) are underway to assess the use of BSGM in patient selection for pylorus-targeted therapy

3. High-resolution manometry

Antroduodenal manometry has been used to evaluate gastric and duodenal motility. During the evaluation of pylorus with conventional manometry using a water-perfused system, a catheter with an additional transpyloric sleeve (Dent sleeve) including pressure sensors closely spaced at 3- to 5-mm intervals is used to measure sphincter pressure while minimizing the effect of catheter movement.⁶⁶ However, monitoring pyloric pressure is technically difficult, requiring experienced operators, as the recording is affected by the location of the pressure sensors and frequent movement and physiological artifacts such as respiratory activity and pulsations from nearby major vessels can lead to interpretation difficulties, especially as the recording duration classically is over 6 hours (4 hours for fasting period followed by standard meal ingestion and next 2 hours for studying postprandial period). Compared to conventional manometry, high-resolution manometry system can provide more details on pyloric pressure during different contraction phase.⁶⁷ Zheng et al.⁶⁸ demonstrated the high-resolution manometry could be used to characterize a variety of dysfunction including postprandial antral contractile and pyloric motility. In one study including 16 patients with suspected gastroparesis, postprandial antral hypomotility was the most common finding in 11 patients, and pyloric spasm was observed in two patients.⁶⁸ With 13 sensors placed across the antro-pyloro-duodenal junction, pylorus could be identified throughout the postprandial hours in all patients.²⁹ Soliman et al.⁶⁹ compared the high-resolution antroduodenal motility profile between 35 patients of normal gastric emptying and 25 patients of delayed gastric emptying using a probe with 36 sensors recording across the pylorus. In that study, pyloric spasm was defined as the presence of repeated isolated pyloric waves occurring for at least 3 minutes. Seventy-two percent of the patients with delayed emptying showed manometric profile alterations. Among them, 56% of patients had low frequency of antral contraction and 32% of patients had pylorospasm. Additionally, 20% of the patients with normal gastric emptying exhibited manometric alterations and 6% of the patients had pylorospasm. The analysis of pyloric parameters revealed that, compared to the patients without delayed gastric emptying, those with delayed gastric emptying had significantly higher peak pyloric pressure (66±40 mm Hg vs 48±16 mm Hg, p=0.04) and a higher mean pyloric pressure in postprandial period (18.9±9.7 mm Hg vs 12.9±5.7 mm Hg, p=0.01). Pylorospasm in the postprandial period was more frequent in patients with delayed gastric emptying group than in those without delayed gastric emptying (32.0% vs 5.7%, p=0.02). To date, only two studies have evaluated the impact of high-resolution manometry in gastroparesis and additional studies are needed. In future, high-resolution manometry is expected to facilitate the characterization of abnormal antro-pyloro-duodenal motility, and to be utilized as a good diagnostic modality for pyloric dysfunction.

4. EndoFLIP

EndoFLIP has been developed to evaluate and identify motility disorders by providing real-time pressure and dimensionality measurements. The principle of EndoFLIP is the use of impedance planimetry to measure multiple cross-sectional areas (CSAs) of hollow structures within a cylindrical bag during volumetric distension. The distensibility and compliance of any sphincter in the gastrointestinal tract can be measured by combining the values of intra-balloon pressure and volume. The EndoFLIP device is composed of a 240 cm-long plastic catheter with serial impedance electrodes, which is enclosed in a polyurethane balloon.⁷⁰ The catheter is inserted, and the balloon is positioned at the pylorus under endoscopic or fluoroscopic guidance. Catheter position is important as the measurements may vary according to the balloon position. Of note, pyloric pressure and CSA values are higher when measured in the proximal position.⁷¹ There are no established cutoff values or normal range for EndoFLIP parameters in the pylorus. For example, in a French study of 21 unanesthetized healthy volunteers, the pylorus-distensibility index (P-DI) was 25.2±2.4 mm²/mm Hg and the pyloric pressure was 9.7±4.4 mm Hg at 40 mL of balloon volume.⁷² In an Indian study including 20 anesthetized healthy controls, the mean P-DI and pyloric pressure were 8.4±4.7 mm²/mm Hg and 23.6±15.3 mm Hg at 40 mL of balloon volume, respectively.⁷³ In another study in the United States, 24 healthy volunteers who underwent EndoFLIP without sedation, the P-DI was 10.9±4.8 mm²/mm Hg at 40 mL of bag inflation.⁷⁴ It is conceivable that variations in parameters observed in healthy volunteers might stem from ethnic/racial differences, operator variability, and/or effects of anesthetics.⁷⁰

Decreased pyloric distensibility has been reported in patients with gastroparesis. Desprez et al.⁷⁵ evaluated pyloric function using EndoFLIP in 46 patients with diabetic gastroparesis, 33 patients with idiopathic gastroparesis, and 21 healthy volunteers. The mean pyloric distensibility at 40 ml of inflation was significantly lower in diabetic group (10.8±0.9 mm²/mm Hg) and in those of idiopathic gastroparesis (14.8±2.2 mm²/mm Hg) than in healthy volunteers (25.2±2.3 mm²/mm Hg) (p<0.005). When altered pyloric distensibility was defined as a value below 10 mm²/mm Hg at 40 mL of inflation, the rate of decreased pyloric distensibility were 56.5% and 51.5% in patients with diabetic and idiopathic gastroparesis, respectively, and only 10% in healthy volunteers. In a prospective study comparing pyloric parameters between 27 gastroparesis patients and 21 healthy volunteers, fasting pyloric compliance was lower in those with gastroparesis than in healthy volunteers (16.9±2.1 mm²/mm Hg vs 25.2±2.4 mm²/mm Hg, p<0.005) and decreased pyloric compliance was inversely correlated with dyspeptic symptoms except bloating.⁷² In a study reported by Malik et al.,⁷⁶ early satiety and postprandial fullness were inversely correlated with diameter and CSA of the pylorus. Decreased P-DI was also observed in patients with chronic nausea and vomiting without delayed gastric emptying, suggesting that pyloric dysfunction might lead gastroparesis-like symptoms.⁷⁷ Several studies reported that fasting pyloric distensibility was inversely correlated with gastric emptying rate in gastroparesis.^72,77 In those studies, delayed gastric emptying was worse in patients with impaired pyloric distensibility than in those with normal pyloric distensibility. The utility of pyloric distensibility in predicting outcomes in several pylorus-targeted therapies was also reported. Impaired pyloric distensibility was associated with favorable outcomes after botulinum toxin (BT) injection (<10 mm²/mm Hg of cutoff value at 40mL of bag inflation),³⁹ pyloric balloon dilation,⁷⁸ and G-POEM (when applied to <9.2 mm²/mm Hg of cutoff value at 50 mL, the sensitivity and specificity were 72.2% and 100%, respectively for clinical success after G-POEM).^79,80 Although many studies have already investigated EndoFLIP due to the growing interest and ease of procedure, additional studies are warranted to clarify normal cutoff values and to perform comparative analyses including other diagnostic modalities used for pyloric dysfunction to determine the utility of EndoFLIP in daily clinical practice.

Despite growing interest in pylorus-targeted therapeutic approaches, most published studies to date have focused on the treatment of gastroparesis without consideration of the specific underlying pathophysiology. In this section, we review the reported treatment modalities based on the existing published data of gastroparesis.

1. Pharmacological agents

There are no current pharmacologic therapies for pyloric dysfunction. Pyloric relaxation is a NO-dependent process, and NO-induced smooth muscle relaxation is mediated by the second messenger cyclic guanosine monophosphate, which is hydrolyzed by tissue phosphodiesterases. Therefore, the phosphodiesterase-5 inhibitor, sildenafil can inhibit cyclic guanosine monophosphate hydrolysis and potentiate NO-mediated pyloric relaxation. Indeed, in a mouse model of diabetes mellitus, sildenafil reversed NO-mediated pyloric relaxation and improved gastric emptying.⁸¹ The effect of sildenafil on gastric emptying in human studies has been inconsistent. In a case report, sildenafil improved gastric emptying in two patients with diabetic gastroparesis.⁸² However, sildenafil was not effective in a study evaluating gastric emptying in 12 patients with end-stage renal failure and gastroparesis.⁸³ It is possible that sildenafil impacts not only the pylorus but also the fundus/body and that the relaxation of fundus/body may oppose the effects of sildenafil on gastric peristalsis.⁸³ However, objective parameters of pyloric function were not evaluated in previous human studies. Future studies should assess the effect of sildenafil in patients with pyloric dysfunction, not in all patients with gastroparesis.

Another potential pharmacologic approach to pyloric dysfunction may be the peripherally active μ-opioid receptor antagonists (PAMORAs), which can reverse opioid-induced gut hypomotility.^15,84 Pyloric contraction induced by duodenal acidification can be inhibited by naloxone injection.^85,86 However, several double-blind randomized controlled trials have shown that PAMORAs like methylnaltrexone, naloxegol, or alvimopan, exert their actions on the small and large intestine, with no effect on opiate-induced delayed gastric emptying.^87-89 Thus, further studies are required to assess the efficacy of PAMORAs in treating pyloric dysfunction.

2. BT injection

BT, a neurotoxin produced by the anaerobic bacterium Clostridium botulinum, was initially approved for the treatment of spasticity observed in numerous disorders.⁹⁰ BT induces muscle relaxation by blocking the release of acetylcholine, the principal neurotransmitter at the neuromuscular junction, as well as all parasympathetic and cholinergic postganglionic sympathetic neurons.⁹⁰ Thus, BT has been used as a treatment option in disorders with smooth muscle over-activity, including gastrointestinal diseases such as achalasia and esophageal and pyloric spasm.^91,92 The effect of BT is reversible, as neuromuscular function is recovered with the sprouting of nerve terminals and the formation of new synaptic contacts.⁹⁰

In early open-label trials, intrapyloric BT injection showed short-term efficacy in alleviating symptoms of gastroparesis and delayed gastric emptying.^93,94 Lacy et al.⁹⁵ performed an open-label trial including eight patients with type I diabetic gastroparesis and age-, sex-matched controls. In that study, pretreatment pylorospasm was noted by antroduodenal manometry in all eight patients with diabetes and none of the healthy volunteers. In five patients with available data, pylorospasm was significantly reduced 12 weeks after BT injection compared to baseline. Tonic pyloric pressure was also reduced after the BT injection, although the difference was not statistically significant. BT led to improvement in symptoms and four out of eight patients showed increased gastric emptying at 12-week follow-up.⁹⁴ Subsequently, two randomized controlled trials including patients with idiopathic, diabetic, and postsurgical gastroparesis failed to show the superiority of BT injection over placebo in symptom improvement and gastric emptying (Table 3).^96,97 One of these trials included 23 patients with gastroparesis in a cross-over design to receive 100 units BT or saline, 1 month apart.⁹⁶ Interestingly, symptomatic improvement and improved gastric emptying was observed both after BT and after the saline injection. In the other controlled trial, 32 patients with gastroparesis were randomized to the BT injection (200 units) or the saline placebo group.⁹⁷ One-month evaluation revealed symptom improvement rates of 37.5% and 56.3% in the BT injection and saline groups, respectively. The BT injection group demonstrated improvement in gastric emptying, although the quantity of improvement from baseline was not significantly different than that in the saline placebo group. Thus, current society practice guidelines do not support routine intrapyloric BT injection as a treatment for gastroparesis;^54,98 however, many centers continue to offer this therapy to selected patients. A systematic review including 15 studies on intrapyloric BT injection for gastroparesis revealed improvement in subjective symptomatic relief and objective gastric emptying measurements, inconsistent with the findings of these two randomized controlled trials.⁹⁹ However, notably, all of these studies on BT did not evaluate pyloric function before treatment or the pathophysiology of gastroparesis, which was likely heterogeneous in these study cohorts.

Table 3 . Summary of Botulinum Toxin Injection Trials.

Author (year)	Study design	No. of patients	Results	Patient population
Ezzeddine et al. (2002)93	Prospective, single arm	6	Improvement in subjective symptom score of 55% Improvement in gastric emptying by 52%	Diabetic gastroparesis
Miller et al. (2002)94	Prospective, single arm	10	Decrease in symptom score by 38% Improvement in mean percentage of solid gastric retention at 4 hr from 27% to 14%	Idiopathic gastroparesis
Lacy et al. (2004)95	Prospective, single arm	8	Mean symptom score improvement from 27 to 12.1 (p<0.01) Reduction in mean GES (339.1 min to 227.3 min, p=0.11)	Diabetic gastroparesis with documented absence of pylorospasm
Arts et al. (2007)96	Double-blind cross-over placebo-controlled trial	23	Improvement in solid GE with first botulinum toxin injection (111 min vs 93 min, p<0.05). No significant symptom improvement between treatment arms (0.8±5.5 vs 24.3±16.6, p=NS)	Idiopathic gastroparesis
Friedenberg et al. (2008)97	Double-blind, placebo-controlled trial	32	No significant improvement in gastric emptying (–13.3% vs -3.6%, p=0.27) or symptoms (37.5% vs 56.3%, p=0.29) compared to placebo	Idiopathic and diabetic gastroparesis

GES, gastric emptying scan; GE, gastric emptying; NS, not significant..

In a recent pediatric study, pyloric function was measured with EndoFLIP before BT injection in children with neurodisabilities and symptoms suggesting delayed gastric emptying. The EndoFLIP parameters of pylorus and symptoms were improved after BT treatment.¹⁰⁰ Desprez et al.³⁹ reported that pyloric distensibility measurement using the EndoFLIP before intrapyloric BT injection can predict symptomatic and quality of life response 3 months after the treatment. Future randomized sham-controlled studies in patients with documented pyloric dysfunction as the main pathophysiology of gastroparesis are needed to confirm the efficacy of intrapyloric BT injection as a targeted therapy.

3. Endoscopic balloon dilation

Endoscopic balloon dilation for pyloric dysfunction, initially reported in children, has been demonstrated to be effective in adults as well.^78,101 The notable advantages of endoscopic balloon dilation are that it is technically more accessible and is associated with fewer complications compared to other pylorus-targeted endoscopic procedures. In one study, 10 patients with gastroparesis and low fasting pyloric compliance on EndoFLIP (<10 mm²/mm Hg) underwent dilation to 20 mm, resulting in increased fasting pyloric compliance after 10 days in all patients (7.4±0.4 to 20.1±4.9 mm²/mm Hg) and improved gastric emptying scintigraphy in seven out of eight patients. Symptoms and quality of life scores were also improved.⁷² However, the effect of pyloric balloon dilation does not seem to result in a sustained treatment effect. In a recent retrospective study of 47 patients with refractory gastroparesis, clinical response was achieved in only 50% of the patients 2 months after the endoscopic balloon dilation and was further decreased to approximately 30% 2 years after the procedure.¹⁰¹

Murray et al.¹⁰² reported clinical outcomes in patients with gastroparesis of combining the diagnostic use of EndoFLIP and the therapeutic use of EsoFLIP (a device that utilizes impedance planimetry technology to provide real-time, objective visualization and monitoring of therapeutic dilation to diameters up to 30 mm). In that study, 46 patients with probable gastroparesis underwent EsoFLIP with individually titrated, controlled pyloric dilation; the authors reported that gastric emptying half-time significantly decreased from a median of 211 to 179 minutes (p=0.001) and that pyloric distensibility improved from 9 to 13 mm²/mm Hg (p<0.001) after the dilation. Bhutani et al.¹⁰³ reported the efficacy of combining therapy of pyloric dilation and intrapyloric BT injection in patients who developed delayed gastric emptying after distal esophagectomy for esophageal cancer. Following the injection of 100 units of BT, dilation was performed for 1 minute with a maximum diameter of 12 to 20 mm. Of the 21 patients, 18 patients (85%) exhibited significant overall improvement in symptoms; the authors inferred that balloon dilation after BT injection might result in improved efficacy by increasing BT diffusion in the pylorus.

4. Transpyloric stent placement

Clarke et al.¹⁰⁴ is the first to report the utility of transpyloric stent insertion for the treatment of gastroparesis in a case series of three young patients with gastroparetic symptoms. The authors reported improvement in symptoms and gastric emptying parameters during a short-term follow-up period after the placement of double-layered, fully covered, self-expandable metallic stents. Additionally, in a retrospective study evaluating the efficacy of transpyloric stent placement with or without stent fixation in 30 patients with gastroparesis, the technical and clinical success rates were 98% and 75%, respectively.¹⁰⁵ However, the very high rate of stent migration is the primary concern in transpyloric stent placement. In one study, stent migration occurred in 100% of the patients without fixation; the migration rate declined to 48%–71% with various fixation approaches such as clipping, endoscopic suturing, and over-the-scope clip application, which is still a high rate of migration.¹⁰⁵ In keeping with this, the European Society of Gastrointestinal Endoscopy recommends against the use of transpyloric stents in the treatment of gastroparesis because of the high rate of stent migration and the potential risk of adverse events such as intestinal obstruction.¹⁰⁶ Before its implementation in clinical practice, further studies are warranted to determine whether stent placement is effective for pyloric dysfunction, to identify patients who might derive the most benefit, to assess the timing for stent removal, and to design specific fully covered stents that prevent distal migration. Finally, prospective randomized controlled trials are needed as current evidence is based on case reports and small retrospective studies.

5. Surgical pyloroplasty

Surgical pyloroplasty is a gastric drainage method for benign gastric outlet obstruction and post-vagotomy stomach.¹⁰⁷ In recent years, several retrospective studies have evaluated the efficacy of surgical pyloroplasty for nonobstructive gastroparesis.^64,108,109 The Heineke-Mikulicz pyloroplasty is the most common technique performed, with the goal of increasing the pyloric channel CSA. It is a minimally invasively operation (laparoscopic or robotic), that consists of a longitudinal full-thickness incision extending from the distal antrum to the proximal duodenum, with a transverse sutured closure. The longitudinal opening should be no less than 5 cm, with no less than 1cm on the duodenal side.

Hibbard et al.¹⁰⁸ reported the efficacy of surgical pyloroplasty in 28 patients with gastroparesis, including 26 patients who underwent laparoscopic Heineke-Mikulicz pyloroplasty and two patients who underwent laparoscopic trans-oral endoscopic circular stapled pyloroplasty. The authors reported that 83% of patients exhibited symptom improvement at 1-month follow-up and that 71% of the patients showed normalized gastric emptying scan (GES).¹⁰⁸ Toro et al.¹⁰⁹ reported similar findings in 50 patients with refractory gastroparesis who underwent laparoscopic Heineke-Mikulicz pyloroplasty. They found postoperative symptom improvement in 82% of the patients and, among 66% of the patients who examined postoperative GES, 96% showed improved gastric emptying. However, the major limitation of both studies was the lack of reliable symptom evaluation. Mancini et al.¹¹⁰ evaluated gastric emptying scintigraphy and gastroparesis carinal symptom index (GCSI) scores in 46 patients with refractory gastroparesis who underwent pyloroplasty, including 42 patients who underwent laparoscopic pyloroplasty, three patients who underwent open pyloroplasty, and one patient who converted from laparoscopic to open pyloroplasty; the postoperative evaluations were conducted 6 to 12 months later.¹¹⁰ Gastric emptying improved in 90% of the patients and normalized in 60% of the patients, and the GCSI scores reflected significant reductions in symptom severity across all nine categories.

Shada et al.¹¹¹ reported the largest retrospective study of laparoscopic Heineke-Mikulicz pyloroplasty in a cohort of 177 patients. Gastric emptying scintigraphy revealed improvement in 86% of the patients and normalization in 77% of the patients. Symptom severity scores were also significantly improved, while intraoperative complications and conversion to laparotomy were not observed. The overall morbidity rate was 6.8%, with a readmission rate of 7%. Postoperative complications included wound infection, suture line bleeding, leakage, and pulmonary embolism. After recovery from pyloroplasty, 10.7% of the patients required subsequent surgical procedures such as gastric stimulator implantation, decompressive gastrostomy and/or feeding jejunostomy, and subtotal gastrectomy. Dumping syndrome is reported up to 15% of the patients after vagotomy and pyloroplasty.^112,113 Recently, Bajpai et al.¹¹⁴ reported that robotic Heineke-Mikulicz pyloroplasty might be as safe and cost-effective as laparoscopic Heineke-Mikulicz pyloroplasty, based on the finding that the operation duration and the length of hospital stay were shorter in patients undergoing robotic Heineke-Mikulicz pyloroplasty (n=23) as compared to the laparoscopic approach (n=9). Although surgical costs were higher in the robotic Heineke-Mikulicz pyloroplasty group, the total cost of the inpatient stay was comparable between the two groups. Based on the reported retrospective studies, surgical pyloromyotomy may be considered a treatment option for pyloric dysfunction. Conversely, no prospective randomized controlled trials have evaluated the efficacy of surgical pyloroplasty for refractory gastroparesis, and none of the published studies to date have specifically evaluated pyloric function before and/or after surgery.

Gastric peroral endoscopic myotomy (G-POEM) has emerged as a promising treatment option in refractory gastroparesis. POEM, initially developed for the treatment of achalasia, has been accepted as a treatment of choice in clinical practice for achalasia because of the high efficacy and low invasiveness.¹¹⁵ Following its introduction for the treatment of gastroparesis by Khashab et al.,¹¹⁶ the clinical efficacy and safety of G-POEM for refractory gastroparesis has been reported (see Clinical success below). Case reports have demonstrated that G-POEM is associated with favorable outcomes regardless of the etiology of gastroparesis.¹¹⁷ In one case report of a patient with pylorospasm, G-POEM led to symptomatic remission during the follow-up period.⁸ Therefore, as a pylorus-targeted therapy, G-POEM is considered an effective treatment option for pylorospasm. However, in patients with a history of opioid use, reevaluation of gastric emptying should be performed after opioid discontinuation before proceeding with G-POEM.

1. Technical aspects

G-POEM is divided into five steps: initial endoscopic inspection, mucosal incision, submucosal tunneling, pyloromyotomy, and closure of the mucosal incision. The G-POEM procedure is shown in Fig. 1. Each step may have some variation depending on the experience and preference of the operating endoscopist. The mucosal incision generally begins on the greater curvature side, 4 to 5 cm prior to the pylorus.^117,118 Access on the greater curvature side is preferred because of the technical ease it provides: the endoscope can be kept in a more neutral position with improved maneuverability. The lesser curvature side is the second preferred approach, albeit more challenging, and the anterior or posterior wall is chosen in rare cases.¹¹⁹ No study to date has compared the impact of specific approach directions on outcomes in G-POEM. A submucosal bleb is created using a mixture of normal saline solution and a dye (methylene blue or indigo carmine). The incision is usually 1.5 to 2 cm in length and may be transverse or longitudinal.¹²⁰ Submucosal tunneling is performed until the pylorus is clearly visualized. Next, pyloromyotomy is performed using an endoscopic knife and the myotomy length is continued until the entire pyloric sphincter is disrupted. Careful attention should be paid to avoid mucosal or deep injury, especially at the pylorus. Next, closure of the mucosal entry is performed using clips or an endoscopic suturing device. The procedure is concluded after checking for bleeding and other potential complications. The reported technical success rate of G-POEM is 100% in most of the published studies,^118,121-123 with no definite technical contraindications. The procedure time, which varies from 40 and 120 minutes depending on the operator experience,^121,124 can be affected by factors contributing to procedural difficulty such as severe submucosal fibrosis and bleeding.

Figure 1. Gastric peroral endoscopic pyloromyotomy (G-POEM) procedure. (A) Pylorus prior to G-POEM. (B) Initial submucosal injection. (C) Mucosotomy. (D) Submucosal tunnel to the pyloric muscle. (E) Completion of the pyloromyotomy. (F) Closure of the mucosotomy via suture. (G) Pylorus after G-POEM.

2. Clinical success and prognostic factors

The reported short-term clinical success rate (defined differently in different studies) after G-POEM ranges between 73% and 90% at 3 months.^79,125-127 Furthermore, the clinical success rate of G-POEM at 12 months ranges between 57% and 70% in retrospective studies^80,128-131 and between 33% and 56% in the prospective studies (Table 4).^118,132,133 In a meta-analysis evaluating mid-term efficacy of G-POEM in 10 studies with 482 patients with a minimum 1-year follow-up period, clinical success was moderate with a rate of 61%.¹³⁴ The considerable discrepancy in clinical response rates among the published reports is due to the variations in the definition of clinical success and the differences in the patient characteristics and the underlying etiology of their gastroparesis. Most published data are from retrospective studies or cohorts without controls, introducing bias, and prospective randomized controlled trials on G-POEM are limited.

Table 4 . Summary of G-POEM Trials.

Author (year)	Study design	No. of patients	Primary outcome	Comments
Jacques et al. (2019)79	Prospective, single arm	20	GCSI improved from 3.5 to 1.3 (p<0.001)	10 Diabetic and 10 non-diabetic patients
Gonzalez et al. (2017)125	Retrospective, single arm	29	GCSI improved from 3.3 to 1 (p<0.001)	15 Idiopathic, 7 diabetic, 5 postsurgical
Malik et al. (2018)126	Retrospective, single arm	13	Symptomatic improvement in 73% of patients	4 Idiopathic, 1 diabetic, 8 postsurgical
Shlomovitz et al. (2015)127	Retrospective, single arm	7	Symptomatic improvement in 85% of patients. Normalized GES in 80% of patients	5 Idiopathic, 2 postsurgical
Mekaroonkamol et al. (2019)128	Retrospective, single arm	40	GCSI improvement from 3.56 to 1.93 (p=0.001)	15 Diabetic, 25 non-diabetic
Ragi et al. (2021)129	Retrospective multicenter, single arm	76	Clinical success rate at 1 year of 65.8% (defined as 1 point improvement in GCSI)	27 Idiopathic, 26 diabetic, 15 postsurgical, 8 others
Abdelfatah et al. (2021)130	Retrospective, single arm	90	Clinical response rate of 81.1%	42 Idiopathic, 38 diabetes, 10 others
Tan et al. (2021)131	Retrospective, single arm	79	Clinical response rate of 81.8% at 24 mo GCSI improvement from 2.97 to 0.88	79 Postsurgical
Vosoughi et al. (2022)118	Prospective, multicenter, single arm	80	Clinical success rate of 56% at 12 mo GCSI improvement from 2.8 to 1.5	33 Idiopathic, 19 diabetes, 28 postsurgical
Conchillo et al. (2021)132	Prospective, open-label	24	Clinical success rate 70.8% at 3 mo, 33.3% at 12 mo GCSI improvement from 3.1 to 1.6	11 Idiopathic, 6 diabetes, 7 postsurgical
Gregor et al. (2021)133	Prospective, single arm	52	Clinical response 68% at 1 mo and 48% at 1 yr GCSI improvement from 3.4 to 1.3	18 Idiopathic, 17 diabetic, 9 postsurgical
Martinek et al. (2022)135	Randomized, sham-controlled trial	41*	Treatment success rate 71% (G-POEM) vs 22% (Sham), p=0.005	11 Idiopathic, 17 diabetic, 13 postsurgical
Gonzalez et al. (2024)136	Double-blind randomized controlled trial	40	Clinical success rate over BTI (65% vs 40%, p=0.10)	18 Idiopathic, 11 diabetic, 6 postsurgical

G-POEM, gastric peroral endoscopic pyloromyotomy; GCSI, gastroparesis carinal symptom index; GES, gastric emptying scan; BTI, botulinum toxin injection..

*Trial stopped after interim analysis by Data and Safety Monitoring Board..

To date, only two randomized controlled trials evaluated the efficacy of G-POEM in gastroparesis. In the first study, Martinek et al.¹³⁵ randomized 41 patients with severe gastroparesis to the G-POEM or a sham procedure group at a ratio of 1:1 and compared procedure efficacy at 6 months. Treatment success was defined as a decrease of at least 50% in the aggregate symptom score; the success rate was 71% in the G-POEM group and 21% in the sham group. Gastric retention at 4 hours decreased from 22% to 12% in the G-POEM group but did not change in the sham group. Of the 12 patients who were randomized to the sham group with persistent symptoms and crossed over to the G-POEM group, eight patients achieved treatment success after pyloromyotomy. The second study by Gonzalez et al.¹³⁶ aimed to compare the efficacy of G-POEM to that of BT injection in a cohort of 40 patients who were randomized into the G-POEM or the BT injection group at a ratio of 1:1. Clinical success was defined as a significant decrease of >1 point in the mean GCSI score compared to the pretreatment GCSI score. The clinical success rates at 3 and 12 months were 65% and 60%, respectively, in the G-POEM group. The postoperative gastric emptying rate was improved in 72% of the patients in the G-POEM group. However, the higher clinical success rate and the improved GES rate observed in the G-POEM group were not significantly different from those observed in the BT injection group. Long-term efficacy beyond 12 months is currently unknown; however, the reported 2-year clinical response ranges from 69.5% to 89.9%.^{129,131,137,138} Recently, Hernández Mondragón et al.¹³⁷ assessed the 4-year efficacy of G-POEM in patients with refractory gastroparesis. Clinical success was defined as an average decrease of ≥1 point in the total GCSI score, with at least two GCSI subscales ≥ 25%. The 4-year clinical success rate was 77.5%, and the quality of life score, determined with the 36-item short form survey (SF-36), was also improved. Additionally, gastric 4-hour retention and mean emptying half-time exhibited improvement 4 years after surgery, and 63.9% of the patients achieved normal stomach emptying.

Most of the studies on G-POEM have demonstrated improvement of gastric emptying, an objective parameter. In retrospective studies, improvement based on gastric emptying scintigraphy after G-POEM ranged from 46% to 90% and normalization ranged from 32% to 75%.^{80,117,125,126,130,139-141} Additionally, gastric emptying half-time is also accelerated^92,135 and retention gastric volume at 4 hours was improved.^123,129,133 Furthermore, G-POEM may be effective in decreasing health care burdens associated with gastroparesis. Several studies reported that patients who underwent G-POEM experienced a significant reduction in numbers of emergency room visits and hospitalization for gastroparesis symptoms.^117,133 Overall body mass index and quality of life, assessed by the SF-36 or the patient assessment of gastrointestinal disorders symptom severity index (PAGI-SYM) questionnaire, significantly improved after G-POEM procedure.^126,130,140

Several studies have suggested that the increased diameter and distensibility index of pylorus after G-POEM are predictive factors for clinical success. Watts et al.¹⁴² evaluated pyloric function before and after G-POEM using EndoFLIP in 20 patients with refractory gastroparesis. After G-POEM, the mean and maximum pyloric diameters and the maximal pyloric distensibility at 50 mL of inflation were increased. Interestingly, the number of phasic contractions remained unchanged after G-POEM. To date, validated cutoff values to determine the normal range of parameters and the diagnostic criteria for pyloric dysfunction using these modalities remain lacking. Treatment plans would ideally be based on objective measurements, such as pyloric CSA, the distensibility index with EndoFLIP, and postprandial pyloric hypercontractile response with high-resolution manometry.¹⁴ Some studies reported that the EndoFLIP measurements are improved after G-POEM.^80,81,143 In a study evaluating the association between the EndoFLIP measurements and the clinical outcome of G-POEM, CSA using 40-mL volume distension performed 3 months after G-POEM predicted clinical success with a specificity of 91% and a sensitivity of 71%.⁸⁰ In a meta-analysis of studies with a minimum 1-year of follow-up, the mean post-procedural distensibility index was significantly higher in patients who experienced clinical success than in those who experienced clinical failure at 40- and 50-mL volume distension.¹³⁴ For the identification of patients who might benefit from pylorus-targeted therapies, more studies are warranted to elucidate the predictive values of the EndoFLIP and high-resolution manometry parameters.

In a recent retrospective study involving a large cohort, long-term clinical success after G-POEM was associated with diabetes etiology, predominant symptoms of nausea and vomiting, a GCSI score of 1.5 to 2.5 at 6 months, and a 4-hour retention rate of <10% at 6 months.¹³⁷ However, Labonde et al.¹³⁸ showed conflicting data suggesting that satiety and bloating symptoms are better predictors of long-term clinical success. They proposed a new predictive score system that includes nausea (<2), satiety (≥4), and bloating (>3.5) subscales of the GCSI and 4-hour percent retention (>50%). A threshold of having 2 of the 4 criteria predicted clinical success with a sensitivity of 93.3% and specificity of 56.3%.

3. Adverse events

G-POEM is a generally safe procedure when performed by trained therapeutic endoscopists. Previous meta-analyses revealed that procedure-related adverse events ranged from 6.1% to 18.4%,^{119,121,122,134,144,145} whereas more recent prospective studies have reported an approximate adverse event rate of 6%.^118,133 When the American Society for Gastrointestinal Endoscopy lexicon’s severity grading system was used, the rate of mild and moderate adverse events was 93% to 98%.^145,146 Additionally, early adverse events within the first 48 hours after the procedure were most common, followed by intra-procedural, and late adverse events (>48 hours after the procedure).¹⁴⁶ The three commonly reported adverse events are capnoperitoneum (2%–4% of patients), mucosotomy (1%–4% of patients), and bleeding (1%–2% of patients).^{118,129,133,145,146} Capnoperitoneum is managed with needle decompression. Mucosotomy and bleeding are usually well-controlled with endoscopic intervention. Several studies reported pyloric ulcers at the mucosotomy site, which could be treated with proton pump inhibitors.¹¹⁹ Other adverse events, including pulmonary embolism, abscess, perforation, and stricture were reported in <1% of the patients.^119,121 There are several reported cases on temporary dumping syndrome after G-POEM but the cases required no specific treatment and it was well controlled by dietary education.^145,147 Mortality associated with the procedure was not reported. As mortality unrelated to the procedure, there was the only one death due to cardiac events was reported within 30 days after G-POEM,¹⁴⁸ establishing G-POEM is a safe treatment modality.¹²⁴ Endoscopist experience with <20 G-POEM procedures was reported as a risk factor for adverse events, suggesting the significant impact of operator experience on G-POEM outcomes.¹⁴⁶

4. Comparison between G-POEM and surgical myotomy

Whether pyloromyotomy is performed endoscopically or surgically is an important consideration. Landreneau et al.¹⁴⁸ compared the efficacy of G-POEM with that of laparoscopic pyloroplasty in patients with medically refractory gastroparesis after propensity score matching. The efficacy was comparable between the surgical pyloroplasty and G-POEM groups, with improvements observed in GCSI scores and gastric emptying studies. However, the G-POEM group experienced better outcomes in average length of hospital stay, operation duration, and estimated blood loss in subgroup analysis, indicating that G-POEM might contribute to reduced procedure-related costs. Although not reaching statistical significance, the rate of adverse events was higher in the surgical group than in the G-POEM group (16.7% vs 3.3%). These results are consistent with those of two recent meta-analyses comparing G-POEM with surgical myotomy,^149,150 which revealed that the clinical efficacy of G-POEM was comparable to that of surgical myotomy, although the mean procedural time and length of hospital stay were significantly lower with G-POEM than with surgical myotomy.¹⁴⁹ Regarding adverse events, the rate of adverse events tended to be higher with surgical myotomy than with G-POEM, without statistical significance,¹⁵⁰ likely due to the small number of patients presenting with adverse events. The profile of adverse events is distinct between the two procedures. While bleeding, capnoperitoneum, and mucosotomy are common adverse events after G-POEM, surgical site infection, leaks, bleeding, and dumping syndrome are common adverse events after surgical myotomy. Importantly, surgical myotomy might be associated with more severe adverse events. In general, patients who underwent G-POEM are considered to have less pain and recover faster compared to those who underwent surgical myotomy.¹²⁴

G-POEM appears to be a promising treatment modality with short- and mid-term efficacy for refractory gastroparesis, and recent studies are investigating the long-term efficiency of G-POEM. As a minimally invasive procedure, the major attraction of endoscopic myotomy over surgery is cost-effectiveness with a good safety profile. However, clinical failure at 6 months ranges between 14% and 44%,^117,118,151 and the reasons for clinical failure include incomplete myotomy, pyloric muscle regeneration (due to incomplete pyloromyotomy), and stricture formation.⁷⁸ Sufficient pyloromyotomy is critical to clinical success. Selective complete pyloromyotomy, identified by clearly exposing the hypomuscular segment that separates the pylorus and duodenal muscularis propria, can be performed without a substantial increase in perforation risk.¹⁵² There is also a suggestion to extend the myotomy proximally 1 to 3 cm into the prepyloric antrum.¹⁵³ Additionally, attention is warranted to prevent mucosal damage and the subsequent pyloric stricture. In a study assessing the long-term efficacy of G-POEM, the annual recurrence rate after the procedure was 4.8% to 14%.¹³⁰ Pyloric muscle regeneration with severe fibrosis is a potential cause of recurrence. Redo G-POEM with a different directional approach may be feasible in these patients. Double pyloromyotomy has been proposed as another option to reduce recurrence. One study reported that clinical success was higher with double pyloromyotomy than with single myotomy during G-POEM (86% vs 68%), without an increase in the procedure time or adverse events.¹⁵⁴ However, the study was conducted in a retrospective setting with short-term observation; thus, further randomized controlled trials with long-term follow-up are warranted to confirm the efficacy of double pyloromyotomy. Furthermore, more studies are needed to increase the clinical efficacy of G-POEM especially in patients with pyloric dysfunction. Well-controlled randomized controlled trials will be important to establish treatment algorithms for these patients.

In summary, accumulating evidences suggest that surgical outcomes are comparable between G-POEM and surgical myotomy and that G-POEM is a more cost-effective procedure with better perioperative morbidity compared to surgical myotomy.

With a growing understanding of the pathophysiology underlying gastroparesis, attention should be paid to specific underlying etiologies when considering the best therapeutic approach. Given that the pylorus has become a novel therapeutic target, further cellular and molecular studies are warranted to elucidate pyloric dysfunction. From a diagnostic standpoint, high-resolution antroduodenal manometry and EndoFLIP have been developed to assess pyloric function; however, inconsistent data regarding their use both the diagnosis and predictive response for the treatment of gastroparesis-induced pylorospasm limits their application at this time. Promising novel methods to evaluate gastric function including WMC and BSGM could help improve diagnosis and define pylorospastic phenotypes in gastroparesis and guide the selection of appropriate pylorus-targeted therapeutic approaches for specific patients. While novel therapeutic options such as G-POEM are emerging, tailoring these approaches based on individual pathophysiologic principles, with an emphasis on long-term safety and outcomes data will be paramount.

J.H.H. is a consultant for Olympus, Medtronic, Boston Scientific, Fujifilm, ERBE, Micro-Tech, Neptune, Lumendi, and EndoRobotics. And he is an editorial board member of the journal but was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.

Study concept and design: J.H.H., H.K.N. Drafting of the manuscript: H.K.N., A.A.L., A.G.B., A.J.P., M.M.E., A.A.J. Critical revision of the manuscript for important intellectual content: L.N., J.H.H. Approval of final manuscript: all authors.